1. Field of the Invention
This invention relates to azetidin-2-one derivatives, and a process for production thereof, and more specifically, to azetidin-2-one derivatives useful as intermediates for carbapenem-type antibiotics such as thienamycin or monocyclic beta-lactam antibiotics, and a process for production thereof.
2. Description of the Prior Art
It is well known that among beta-lactam anti-biotics, optically active compounds having a specific configuration have particularly good antimicrobial activity and beta-lactamase inhibiting activity. It has been strongly desired therefore to develop a process for producing such compounds.
Conventional methods for the production of optically active 4-substituted azetidin-2-one derivatives useful as synthesis intermediates for these beta-lactam antibiotics include, for example, (a) the utilization of natural amino acids such as L-aspartic acid [Hetero-cycles, 14, 1077 (1980)], and (b) the enzymatic hydrolysis of a prochiral beta-aminoglutaric acid diester to a half ester followed by cyclization [J. Am. Chem. Soc., 103, 2405 (1981)].
It may be feasible to use a different method which comprises using a 3-unsubstituted azetidin-2-one derivative having a leaving group at the 4-position as a starting material, and introducing a desired substituent stereoselectively into the 4-position of the starting material. For example, many prior attempts have been known in which these azetidin-2-one derivatives are reacted with various alkyl anions to alkylate the 4-position. All of them, however, are non-asymmetric methods, and none are directed to the production of optically active compounds [J. Chem. Soc., PT, 1981, 1884; Tetrahedron Letters, 22, 1161 (1981); Chem. Pharm. Bull., 28, 3494, 1980; J. Chem. Soc., Chem. Comm., 1981, 1076]. As a method of this type for stereoselectively introducing a 4-position substituent, Japanese Laid-Open Patent Publication No. 152866/1983 discloses a process for producing optically acive 4-phenylthioazetidin-2-one, which comprises reacting a 3-unsubstituted azetidin-2-one derivative with thiophenol in the presence of an optically active base (cinchonidine). According to this method, however, the substituent is not bonded to the 4-position directly through carbon.
On the other hand, many attempts have been made to alkylate the 4-position of a beta-lactam compound having a hydroxyethyl group at the 3-position of the beta-lactam ring and a leaving group at the 4-position thereof by reacting it with an alkylating agent, as schemcatically shown below. ##STR3##
For the production of an optically active diastereomer of the compound (b) in this reaction scheme, a method is known which comprises preparing the optically active compound (a) from 6-aminopenicillic acid, L-aspartic acid or D-allothremin, and then stereoselectively introducing an alkyl group into the 4-position of the compound (a) [Chem. Pharm. Bull., 29, 2899, 1981; Tetrahedron Letters, 23, 2293, 1982; Tetrahedron Letters, 21, 4473, 1980; Tetrahedron Letters, 22, 5205, 1981].
Another method which may be feasible is to produce a racemate of the compound (b) in accordance with the reaction scheme (A) using a racemate of the compound (a) as a starting material and then converting its alkyl group to form carbapenem, etc., and to optically resolve the resulting compound in any of the steps.
In order to obtain carbapenem-series antibiotics having carba-2-penem-3-carboxylic acid of the following formula ##STR4## as a basic skeleton, it has previously been proposed to use the azetidin-2-one derivatives obtained by the aforesaid methods as starting materials. They include, for example, a compound having no substituent (the basic skeleton itself) [for example, J. Antibiotics, 35 (6), 653 (1982), JACS 100 (25), 8006 (1978)], compounds having substituents at the 2-position [for example, Tetrahedron Letters, 21, 2013 (1978)], compounds having substituents at the 6-position [for example, JACS 100 (25), 8004 (1978)], and thienamycin-series compounds having substituents at the 2- and 6-positions (for example, Japanese Laid-Open Patent Publications Nos. 87390/1978 and 32879/1983). These compounds basically have no substituent at the 1-position and show some degree of antimicrobial activity. Basically have no substituent at the 1-position.
On the other hand, as compounds having substituents at the 1-position, compounds having 1 or 2 substituents such as an alkyl, cycloalkyl, acyl, alkoxycarbonyl or cyano group at the 1-position have been reported (for example, Japanese Laid-Open Patent Publications Nos. 69586/1980, 130884/1984, 51286/1984, 93981/1982, and 84887/1984). Of these, (1R, 5S, 6S)-2-(2-N,N-dimethylamino-2-iminoethylthio)-6-[(1R)-1-hydroxyethyl]-1-met hyl carba-2-penem-3-carboxylic acid having a beta-coordinated methyl group at the 1-position is known as an antibiotic having markedly improved resistance to decomposition and inactivation by kidney dehydropeptidase while carbapenem-series antibiotics are commonly susceptible to decomposition and inactivation by kidney dehydropeptidase [Heterocycles, 21(1), 29(1984)].
Although carbapenem-series antibiotics having various substituents at the 1-position either directly or through hetero atoms are expected to have excellent antimicrobial activity, they have not been investigated at all, and no method for production thereof has been developed.